PROJECT SUMMARY (Description): This project seeks to identify the pathogenic actions of microglia and Th17 lymphocytes in infection-sensitized hypoxia-ischemia (HI) brain injury of newborns, including their interactions and strategies for intervention. The combination of prenatal infection and hypoxia-ischemia is a severe threat to immature brains, and often causes death or permanent neurological deficits. Better understanding the mechanisms of infection-sensitized neonatal HI injury is needed to design more effective therapies of this important neonatal disorder. Based on strong preliminary results, we hypothesize that the combination of systemic inflammatory responses and HI promotes early onset of Th17 cells in neonatal brains. The Th17 cell cytokines and tPA (tissue plasminogen activator)-mediated sensitization of endotoxin signaling greatly enhances microglial activation, which not only causes severe brain injury but also fosters the maturation of Th17 cells. We will test this hypothesis in two specific aims. Aim 1 addresses the unique responses of microglia/monocytes to infection-HI and their effects on Th17 cell maturation. Aim 2 addresses the functions Th17 cells in infection-HI and their effects on microglia and monocyte activation in this condition. In sum, this project will determine the mechanisms of microglia-Th17 cell crosstalk in neonatal infection/HI brain injury, and provide the scientific basis for potential new therapies.